My research group, working at Argonne National Laboratory, has implemented a combined quantum (MOPAC-AM1) and molecular mechanics (CHARMM) method to study condensed phase chemical reactions. This method enables the study of electronic structure changes that occur for reactions in complex heterogeneous environments which includes enzyme reactions. We have applied our methods to the enzyme malate dehydrogenase (MDH) to determine the reaction mechanism and find the minimum energy pathway and transition state for the reaction. Our simulations suggest a sequential mechanism that consists of a proton transfer followed by a hydride transfer. Our calculations provide essential information about the mechanism of this enzyme, which is difficult to obtain from traditional experiments. These simulations and methods will be used in the next phase to explain the results of enzyme redesign experiments on lactate dehydrogenase (LDH) and MDH. Specifically, a single amino acid change in LDH has been shown to produce an effective MDH. However, an analogous change in MDH does not produce an effective LDH, even though the structures of the active sites of these two enzymes are essentially identical. We will use our methods to investigate the differneces in the catalytic properties of MDH, LDH, and their mutants. Our simulations of the mechanism of MDH produced a molecular dynamics trajectory that included the bond -making and -breaking events in the enzyme. Since we use a quantum mechanical method to treat the electronic structure changes, we obtained data for the electron density changes as well as the alterations in the coordinates of the atoms during the course of the enzyme reaction. We used the visualiztion and animation facilities at the Cornell Theory Center to produce an animation of the enzyme reaction in malate dehydrogenase. The resultant animation provided insights into the details of the dynamic and structural changes that occur during the enzyme reaction that are impossible to determine from the values of the energies produced by the simulation.